2-acyl hydrazino benzodiazepines

ABSTRACT

L - PHENYL - 4H - S-TRIAZOLO(4,3-A)(BENZODIAZEPINES OF THE FORMULA IV:   1-R,6-(R2,R3-PHENYL),4-R1,R4,R5-4H-S-TRIAZOLO(4,3-A)(1,4)-   BENZODIAZEPINE   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, PHENYL, BENZYL AND -COOR&#39;&#39; IN WHICH R&#39;&#39; IS ALKYL OF 1 TO 4 CARBON ATOMS, INCLUSIVE, WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND WHEREIN R2, R3, RJ AND RK ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKOXY, ALKYLTHIO, ALKYLSULFINYL, ALKYLSULFONYL, ALKANOYLAMINO AND DIALKYLAMINO IN WHICH THE CARBON CHAIN MOIETIES ARE OF 1 TO 3 CARBON ATOMS, INCLUSIVE, ARE PRODUCED BY CONDENSING A 1,3-DIHYDRO-5-PHENYL2H-1,4-BENZODIAZEPINE-2-THIONE OF THE FORMULA I:   2-(S=),5-R1,5-(R2,R3-PHENYL),R4,R5-1,3-DIHYDRO-2H-1,4-   BENZODIAZEPINE   WHEREIN R1, R2, R3, R4 AND R5 ARE DEFINED AS ABOVE, WITH AN ORGANIC ACID HYDRAZIDE OF THE FORMULA:   NH2-NH-CO-R   WHEREIN R IS DEFINED AS ABOVE. THE NEW PRODUCTS OF FORMULA IV INCLUDING THEIR PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS ARE USEFUL AS SEDATIVES, TRANQUILIZERS AND MUSCLE RELAXANTS IN MAMMALS AND BIRDS.

United States Patent US. Cl. 260-239 BD 3 Claims ABSTRACT OF THEDISCLOSURE 6 phenyl 4H s-triazo1o[4,3-a][l,4]benzodiazepines of theFormula IV:

N R-{2\3N N 10 9 R l in, R4

Ra (IV) wherein R is selected from the group consisting of hydrogen,alkyl of 1 to 3 carbon atoms, inclusive, phenyl, benzyl and COOR inwhich R is alkyl of 1 to 4 carbon atoms, inclusive; wherein R isselected from the group consisting of hydrogen and alkyl of 1 to 3carbon atoms, inclusive; and wherein R R R and R are selected from thegroup consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive,halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkanoylamino and dialkylamino in whichthe carbon chain moieties are of 1 to 3 carbon atoms, inclusive, areproduced by condensing a 1,3-dihydro-5-phenyl-2l-I-l,4-benzodiazepine-Z-thione of the Formula I:

H i a /1 8 l R 3 R1 7 l wherein R R R R and R are defined as above, withan organic acid hydrazide of the forumla:

I HgN-NH- (.L-R (II) wherein R is defined as above.

The new products of Formula IV including their pharmacologicallyacceptable acid addition salts are useful as sedatives, tranquilizersand muscle relaxants in mammals and birds.

CROSS REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of application Ser. No. 807,933, filed Mar. 17,1969, now abandoned 3,741,957. Patented June 26, 1973 "ice and adivision of application Ser. Oct. 29, 1969.

BACKGROUND OF THE INVENTION Field of the invention No. 872,394, filedwherein R is selected from the group consisting of hydrogen, alkyl of 1to 3 carbon atoms, inclusive, phenyl, benzyl and -COOR' in which R isalkyl of 1 to 4 carbon atoms, inclusive; wherein R is selected from thegroup consisting of hydrogen and alkyl of 1 to 3 carbon atoms,inclusive; and wherein R R R and R are selected from the groupconsisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive,halogen, nitro, cyano, trifluromethyl, and alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, al=kanoylamino and disalkylamino in whichthe carbon chain moieties are of 1 to 3 carbon atoms, inclusive.

The process of this invention comprises: condensing a 1,3dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione of Formula I in anorganic solvent, e.g., a lower-alkanol of 1 to 4 carbon atoms,inclusive, or cyclohexanol with an acid hydrazide II, at a temperaturebetween 60 and C. to give a mixture containing the corresponding 2(2-acylhydrazino)-5-phenyl-3H-1,4-bezodiazepine of Formula III and thecorresponding 6 phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine (IV).Under vigorous conditions IV is obtained predominately. The partiallycondensed compound of Formula III'can be separated from IV byconventional methods such as extraction,

chromatography, crystallization and the like, and can be converted tothe corresponding triazolo [4,3-a] [1,4] benzodiazepine (IV) by heatingit up to and above the melting point. Alternatively, the first obtainedmixture of III and IV may be heated above the melting point to convertthe partially condensed Compound III to Compound IV.

3 DESCRIPTION OR THE PREFERRED EMBODIMENT Lower alkyl groups of 1 to 3carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl andisopropyl.

Alkyl of 1 to 4 carbon atoms includes the above radicals as well asbutyl and isomers thereof.

The carbon chain moiety of alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, dialkylamino which is of 1 to 3 carbon atoms, inclusive,is defined as lower-alkyl of 1 to 3 carbon atoms, inclusive, above.

The alkanoylamino group of 1 to 3 carbon atoms consists of formamidoacetamido and propionamido.

The term halogen includes fluorine, chlorine, bromine and iodine.

The novel compounds of the Formula IV including acid addition saltsthereof have sedative, tranquilizing and muscle relaxant elfects inmammals and birds.

The acid addition salts of compounds of Formula IV contemplated in thisinvention, are the hydrochlorides, hydrobromides, hydroiodides,sulfates, phosphates, cyclohexanesulfamates, methanesulfonates and thelike, prepared by reacting a compound of Formula IV with thestoichiometrically calculated amount of the selected pharmacologicallyacceptable acid.

Sedative effects of 8chloro-1-methyl-6-phenyl-4I-I-striazolo[4,3-a][1,4]benzodiazepine areshown by the following tests in mice:

Chimney test: [Med. Exp. 4, 11 (1961)]: The effective intraperitonealdosage for 50% of mice (ED is 0.09 mg./kg. The test determines theability of mice to back up and out of a vertical glass cylinder within30 seconds. At the efiective dosage, 50% of the mice failed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climp out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestransquilization. ED equals the dose of test compound at which 50% ofthe mice remain in the dish. The ED (intraperitoneal administration) inthis test was 0.15 mg./ kg; the, oral ED is 0.045 mg./kg.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Transquilized mice will stay on the pedestal for more than 1 minute. TheED (intraperitoneal administration) is 0.20 mg./kg.; the ED (oraladministration) is 0.9 mg./kg.

Nicotine antagonism test: Mice in a group of 6 are injected with thetest compound (8-chloro-l-methyl-6- phenyl 4H-s-triazolo[4,3-a][l,4]benzodiazepine) Thirty minutes later the mice including control(untreated) mice are injected with nicotine salicylate (2 mg./kg.). Thecontrol mice show overstimulation, i.e., (1) running convulsionsfollowed by (2) tonic extensor fits; follows by (3) death. Anintraperitoneal dosage of 0.1 mg./kg. of the test compound protected 50/of the mice against (2) and (3) (E13 the oral ED is 0.04 rug/kg.

Antagonism to stychnine (as sulfate): The effective dosage ED of8-chloro-1-methyl-6-phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine is1 mg./kg. orally in mice. The test consists in orally administering intogroups of 6 mice the test compound, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a] [l,4]benzodiazepine, and 30 minutes later 3 mg./kg.styrchuine sulfate intraperitoneally. The survivors after 4 hoursreflect the activity of the compound as am uscle relaxant andantispasmodic. A dosage of 3 mg./kg. of strychnine sulfate is routinelyfatal to all the control mice. The following compounds have (byintraperitoneal injection) ED as shown in the table below.

ED (in mg./kg.)

Compound Ch D P Ni 8 chloro 1 methyl 6 (2,6 difluoro- Ehenyl) 4H striazolo[4,3 a}[l,4]-

enzodiazepine 0. 009 0.016 0.020 0.018 8 chloro -1- ethyl 6 phenyl 4H 2triazolo[4,3 a][l,4]benz0diazepine 0.8 0.9 0.9 0.2 8 chloro 6 phenyl 4Hs triazolo [t,3-al[1,4]benzodiazopiue 0. 25 0. 4 0.7 0.08 8trifiuoromethyl 1 methyl 6 henyl 4H s triazolo[4,3 a] 1,4]benzodiazepine0.16 0.16 0.22 0.08 8 chloro 1 methyl 6 (o chloro phenyl) 4H striazolo[4,3 ][1,4]- beuzodiazepine 0.05 0. 028 0. 045 0. 008 8 chloro 1methyl 6 (0 -fluoro phenyl) 4H s triazolo[4,3 a][1,4] benzodiazepine 0.046 0. 056 0. 0% 0. 000

No'rE.Oh=Cl1imney test; D=Dish test; P=Pedestal test; Ni= Nicotineantagonism (3) test.

The pharmaceutical forms contemplated by this invention includepharmaceutical compositions suited for oral, parenteral and rectal use,e.g., tablets, powder packets, cachets, drages, capsules, solutions,suspensions, sterile injectable forms, suppositories, bougies, and thelike. Suitable diluents or carriers such as carbohydrates (laccose),proteins, lipids, calcium phosphate, cornstarch, stearic acid,methylcellulose and the like may be used as carriers or for coatingpurposes. Oil, e.g., coconut oil, sesame oil, saffower oil, cottonseedoil, peanut oil may be used for preparing solutions or suspensions ofthe active drug. Sweetening, coloring and flavoring agents may be added.

For mammals and birds food premixes, with starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared.

As tranquilizer the compounds of Formula IV can be used in dosages of0.01 mg.-2.0 mg./-kg. in oral or injectable preparations as describedabove, to alleviate tension and anxiety in mammals, or birds, such ase.g., occurs when animals are in travel.

Other acid addition salts of the compounds of Formula IV can be madesuch as the fiuosilicic acid addition salts which are usefulmothproofing compounds or the trichloroacetates useful as herbicidesagainst Johnson grass,

Bermuda grass, yellow foxtail and green foxtail, and quack grass.

The starting materials of Formula -I of this invention, substituted orunsubstituted 1,3-dihydro-5-phenyl-2H-1,4- benzodiazepine-2-thiones, aredescribed by G. A. Archer and L. H. Sternbach [1. Org. Chem. 20, 231(1964) and US. Pat. 3,422,091]. These compounds (I) are made by thereaction of the known substituted or unsubstituted 1,3-dihydro-S-phenyl-ZH-1,4-benzodiazepin-2-ones by heating with phosphoruspentasulfide in pyridine for about 45 minutes (Archer et al., ibid.).The following comounds of Formula I are representative startingmaterials:

7-trifluoromethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-Z-thione;

9-trifiuoromethyl-1,3-dihydro-5-[p(propionylamino)phenyl]-2H-1,4-benzodiazepine-Z-thione;

7-cyano-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2- thione;

8-cyano-1,3-dihydro-5- [p-(trifiuoromethyl)phenyl]-2H-1,4-benzodiazepine-Z-thione;

'l-chloro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione;

6-ethylthio-1,3-dihydro-5-(o-bromophenyl) -2H-1,4-

benzodiazepine-Z-thione;

6,8-dichloro- 1,3-dihydro-5-(o-fluorophenyl)-2H- 1,4-

benzodiazepine-Z-thione;

8-propoxy-7-bromo-1,3 -dihydro-5 [m-(ethylsulfineyl)phenyl]-2H--1,4-benzodiazepine-Z-thione;

9-diisopropylamino-7-methyl-1,3-dihydro-5-[m-(propylsulfonyl)-phenyl]-2H-1,4-benzodiazepine-Z-thione;

7-bromo-1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepine-Z-thione;

3-methyl-1,3-dihydro-5- (o-fluorophenyl)-2H-1,4-benzodiazepine-Z-thione;

7-fiuoro-1,3-dihydro-5-(o fluorophenyl)2I-I-1,4-benzodiazepine-2-thione;

3-methyl-1,3-dihydro-5- (p-fiuorophenyl)-2H-1,4-benzodiazepine-Z-thione;

7-nitro-1,3-dihydro-5- (o-chlorophenyl) 2H-1,4-benzodiazepine-Z-thione;

8-nitro-1,3-dihyro-5-(o-chlorophenyl) -2H-1,4-benzodiazepine-Z-thione;

7-bromo-1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-Z-thione;

7-methylsulfinyl-1,3-dihydro-5-(o-fiuorophenyl) -2H-1,4-

benzodiazepine-Z-thione;

7-methyl-1,3 -dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-Z-thione;

7-methylthio-1,3 -dihydro-5-phenyl-2H-1,4-benzodiazepine-Z-thione;

7 -cyano- 1 ,3-dihydr-5- (o-chlorophenyl-2H-1,4-benzodiazepine-Z-thione;

3 ,6,8-trimethyl-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-

benzodiazepie-Z-thione;

9-propylsulfonyl-7-methyl- 1, 3 -dihydro-5-phenyl-2H- l ,4-

benzodiazepine-Z-thione;

7-trifluoromethyl- 1 ,3-dihydro-5- (o-chlorophenyl) -2H- 1,4-

benzodiazepine-Z-thione;

7-dirnethylamino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-Z-thione;

7-fiuoro-1,3-dihydro-5-(o-chlorophenyl) -2H-1,4-benzodiazepine-Z-thione;

7,8-dicyano- 1,3-dihydro-5- [p- (methylsulfonyl) phenyl1-2H-1,4-benzodiazepine-Z-thione;

6,9-dichloro-1,3-dihydro-5-(p-isopropylphenyl)-2H-1,4-

benzo diazepine-Z-thione;

6,8-diethyl-1,3 -dihydro-5- (m-ethylphenyl)-2H-1,4-

benzadiazepine-Z-thione;

6-nitro-1,3-dihydro-5-(o-cyanophenyl)-2H-1,4-benzodiazepine-Z-thione;

7,9-bis(dipropylamino)-1,3-dihydro-5-(o-nitrophenyl)--2H-1,4-benzadiazepine-2-thione;

9-acetylamino-1,3-dihydro-5-(p-cyanophenyl)-2H-1,4-

benzodiazepine-Z-thione; and the like.

In carrying out the process of the invention, a selected1,3-dihydro-5-phenyl-2H-l,4-benzodiazepine-Z-thione (I) in an inertorganic solvent, preferably in a lower-alkanol, e.g., methanol, ethanol,l-propanol, 2-propanol, l-butanol, Z-butanol or the like is heated tobetween 60120 0., preferably to the reflux temperature of the mixture,with the selected acid hydrazide NH NH-COR (II) defined as above. In thepreferred embodiment of this invention the acid hydrazide is used inexcess such as from 2 to 5 times the theoretically required amount, butthe reaction is operative with smaller or larger amounts. The reactionperiod is between 1 and 48 hours. At the termination of the reaction thereaction mixture can be evaporated 0t give a crude product consisting ofthe desired 6-pheny1-4H- s-triazo'lo[4,3-a][1,4]benzodiazepine (IV) andthe partially condensed compound, a 2-(2 acylhydrazino) 5-phenyl-3H-1,4-benzodiazepine (III), which can be separated from eachother, usually by their different solubility in an organic solvent,e.g., methylene chloride, chloroform, carbon tetrachloride, ethylacetate, mixtures thereof and the like. The Compound III afterseparation can be converted to Compound IV by heating it above themelting point of Compound IV for 1 to 10 minutes. In a more simplemanner the crude mixture of Compounds III and IV is heated to ZOO-275C., thereby converting all of Compound III to Compound IV. The crudeCompound IV is then purified by standard methods, e.g., chromatographyor recrystallization from solvents such as ethyl acetate, methylenechloride, chloroform, acetonitrile 01 the like.

The following examples are illustrative of the processes and products ofthe present invention, but are not to be construed as limiting.

PREPARATION I 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)2H-1,4-benzodiazepin-2-one (A) Z-acetamido 5 chloro 2'6difluorobenzophenone.-To a solution of 114 g. (1.0 mole) ofm-difiuorobenzene in 800 ml. of dry tetrahydrofuran cooled to 50 C. andmaintained under a nitrogen atmosphere was added, with stirring, 320 ml.of an n-heptane solution of n-butyl lithium containing 1.0 mole of thelatter. The addition was carried out during 50 minutes and was followedby stirring 2 hours more at 50 C. The cold solution was then added withstirring during 50 minutes to a solution of 187.8 g. (0.97 mole) of6-chloro-2-methyl-4H-3,1- benzoxazin-4-one [1. Am. Chem. Soc. 70, 2423(1948)] in 1400 ml. of benzene and 1000 ml. of tetrahydrofuran at 25 C.The mixture was stirred under a nitrogen atmosphere for 20 hours, atwhich time 1000 ml. of 2 N hydrochloric acidwas added. The aqueous layerwas separated and discarded. The organic layer was filtered to removesuspended solid material and the filtrate was washed with cold, diluteaqueous sodium hydroxide solution. Three layers were present, a lightcolored aqueous phase, a dark brown aqueous phase, and an organic phase.The organic phase, after being dried with anhydrous sodium sulfate, wasconcentrated to give 101 g. of a semi-solid which was then extractedwith 2100 ml. of hot Skellysolve B hexanes. Evaporation of the extractgave 39.9 g. of crude product of melting point 1'06116 C.Recrystallization of this material from Skellysolve B gave purifiedZ-acetamido-S-chloro-2',6'-difluorobenzophenone of melting point 118120C.

Analysis.Calcd. for C H CIF NO (percent): C, 58.17; H, 3.25; CI, 11.45;F, 12.27; N, 4.52. Found (percent): C, 58.11; H, 3.38; CI, 11.53; F,12.24; N, 4.20.

(B) 2 amino-5-chloro2',6-difluorobenzophenone.-A suspension of 4.2 g.(0.014 mole) of Z-acetamido-S- chloro-2,6'-difluorobenzophenone in 350m1. of concentrated hydrochloric acid and 350 ml. of water was heated ona steam bath with stirring and in a nitrogen atmosphere until completesolution resulted. The solution was cooled and basified with 50% aqueoussodium hydroxide solution. The resulting solid was removed by extractionwith methylene chloride. The extract was dried with anhydrous sodiumsulfate and evaporated to dryness. The residue was recrystallized fromcyclohexane to give 2.4 g. of2-amino-5-chloro-2',6'-difluorobenzophenone of melting point 103-105 C.

Analysis.Calcd. for C H clF NO (percent): C, 58.33; H, 3.01; CI, 13.24;F, 14.20; N, 5.23. Found (percent): C, 58.33; H, 3.29; Cl, 13.31; F,14.87; N, 5.14.

(C) 2-(2 bromoacetamido)-5-chl0ro-2",6'-difluorobenzophenone.-To asolution of 2.7 g. (0.01 mole) of2-amino-5-chloro-2',6'-difluorobenzophenone in 100 ml. of benzene,through which a rapid stream of nitrogen was passed, was added 3.03 g.(0.015 mole) of bromoacetyl bromide. A precipitate formed soon after theaddition was complete. The benzene was removed by evaporation and thesolid residue was recrystallized from cyclohexane to yield 3.4 g. of2-(2-bromoacetamido)-5chloro-2',6- difluorobenzophenone of melting point146-147.5 C.

Analysis.-Calcd. for C I-I BrClF NO (percent): C, 46.36; H, 2.23; Br,20.56; Cl, 9.12; F, 9.78; N, 3.60. Found (percent): C, 46.46; H, 2.48;Br, 20.68; Cl, 9.21; F, 9.49; N, 3.82.

(D) 2 (2 aminoacetamido)-5-chloro-2',6'-difluorobenzophenone.-Liquidammonia (3500 ml.) was added to a solution of 26 g. (0.067 mole) of2-(2-bromoacetamido)-5-chloro-2',6'-difluorobenzophenone in 350 ml. ofmethylene chloride. The solution was stirred under reflux for 5 hoursand was then stirred for about 16 hours while excess ammonia evaporated.The methylene chloride solution was filtered to remove solid materialand was then evaporated to dryness. The residue was recrystallized from2 l. of cyclohexane to obtain 19.4 g. of 2- (2-aminoacetamido) 5 chloro2,6' difluorobenzophenone of melting point 133-135 C.

Analysis.Calcd. for C- H CIF N O (percent): C, 55.48; H, 3.42; Cl,10.92; F, 11.70; N, 8.63. Found (percent): C, 56.69; H, 3.99; Cl, 11.19;F, 11.06; N, 8.34.

(E) 1,3 dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-2-one.A solution of 21.0 g. (0.065 mole) of 2(Z-aminoacetamido)-5-chloro-2',6 -difluorobenzophenone in 300 ml. ofpyridine was heated under reflux in a nitrogen atmosphere for 18 hours.The pyridine was removed by evaporation. The residue after being washedwith Skellysolve B hexanes was recrystallized, first from ethylacetate-Skellysolve B hexanes and then from ethyl acetate. There wasthus obtained a first crop (11.7 g.; melting point 248-249 C.) and asecond crop (2.3 g.; melting point 244-246 C.) of 1,3-dihydro-7-chloro-5-(2,6 difluorophenyl)-2H-1,4-benzodiazepin-2- one.

Analysis.Calcd. for C H ClF N O (percent): C, 58.74; H, 2.96; Cl, 11.56;F, 12.39; N, 9.14. Found (percent): C, 58.89; H, 2.78; CI, 11.39; F,11.72; N, 8.95.

This material was found to contain 1.9% ethyl acetate of solvation.Recrystallization of the solvated material from ethanol providesunsolvated 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-2-one.

PREPARATION 2 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-Z-thione A solution of 7.65 g. (0.025 mole) of1,3-dihydro-7- chloro 5 (2,6-difluorophenyl(-2H-1,4-benzodiazepin-2- onein 500 ml. of pyridine was treated with 5.55 g. (0.025 mole) ofphosphorus pentasulfide and heated under reflux in a nitrogen atmospherefor two hours. The pyridine (350 ml.) was removed in vacuo and thethus-produced residue was poured onto crushed ice. The aqueous phase wasextracted with methylene chloride and then discarded. The extract waswashed successively with three ZOO-ml. portions of water and 100 ml. ofbrine, and dried over anhydrous sodium sulfate. Removal of the solventgave 7.0 g. of solid which was recrystallized from ethanolwater, to givein 2 crops 6.8 g. of crude material which, after recrystallization fromethanol-water, gave pure 1,3- dihydro-7chloro-5-(2,6difluorophenyl)-2H-1,4-benzodiazepine-Z-thione of melting point222.5-224 C.

Analysis.-Calcd. for C H ClF N S: (percent): C, 55.82; H, 2.81; Cl,10.98; F, 11.77; N, 8.68; S, 9.93. Found (percent): C, 56.13; H, 2.68;Cl, 11.13; F, 11.69; N, 8.40; S, 9.84.

8 PREPARATION s 1,3-dihydro-7-(trifluoromethyl)-5-phenyl-2H-1,4-benzodiazepine-Z-thione A stirred mixture of1,3-dihydro-7-trifluoromethyl-S- phenyl-2H-1,4-benzodiazepin-2-one (89.7g.; 0.294 mole), dry pyridine (2300 ml.) and phosphorus pentasulfide(72.4 g.; 0.323 mole) was refluxed under nitrogen for 30 minutes, cooledand concentrated in vacuo. A suspension of the residue in ice water wasextracted with methylene chloride. The extract was dried over anhydrouspotassium carbonate and concentrated. The residue was crystallized frommethylene chloride-ethanol to give 43.2 g. of melting point 228.5-229 C.(dec.) and 17.8 g. of melting point 22923-0 C. (dec.) (64.5%) of1,3-dihydro-7- (trifluoromethyl) 5phenyl-2H-1,4-benzodiazepine-Z-thione. The analytical sample prepared byrecrystallization from methylene chloride-ethanol had a melting point of223.5 C. (dec.).

Analysis.Calcd. for C H F N S (percent): C, 60.00; H, 3.46; F, 17.79; N,8.75; S, 10.01. Found (percent): C, 59.85; H, 3.73; F, 17.83; N, 8.42;S, 10.26.

EXAMPLE 1 8-chloro-l-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine (A) 2-(Z-acetylhydrazino)-7-chloro 5 phenyl-3H-1,4-benzodiazepine.-A mixture of 2.0 g. (0.0070 mole) of7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine- 2-thione, 1.55 g.(0.021 mole) of acetic acid hydrazide and 70 ml. of absolute ethanol wasrefluxed for 24 hours with a slow stream of nitrogen bubbling throughthe mixture. The mixture was then concentrated to give a residue. Asuspension of this residue in methylene chloride was filtered.Concentration of the filtrate and crystallization of the residue fromethyl acetate gave 0.65 g. of 2-(2- acetylhydrazino)-7-chloro 5-phenyl-3H-1,4-benzodiazepine of melting point 196197 C. (dec.). Theanalytical sample of melting point 199-200 C. (dec.) was prepared byrecrystallizing some of this material from methylene chloride-ethylacetate. The ultraviolet spectrum (ethanol) had end absorption A max.262 (e=26,900) and 336 (e=1,950) and an inflection at 210 m (e=28,200).

Analysis.-Calcd. for C H ClN O (percent): C, 62.48; H, 4.63; Cl, 10.85;N, 17.15. Found (percent): C, 62.20; H, 4.63; Cl, 11.13; N, 16.99.

Crystallization of the solid from the methylene chloride filtrate gave0.73 g. of a mixture of 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine and 8-chloro-1- methyl-6-phenyl4H s-triazolo[4,3-a] [1,4]benzodiazepine.

(B) 8-chloro-l-methyl 6 phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.A sample of 2-(2-acetylhydrazino)-7-chloro 5phenyl-3H-1,4-benzodiazepine was heated under nitrogen at 250 C. for afew minutes. Crystallization of the cooled melt from ethyl acetate gave8-chloro-l-methyl-6-phenyl 4H s-triazolo[4,3-a][1,4] benzodiazepine ofmelting point 228228.5 C. The ultraviolet spectrum (ethanol) had endabsorption 7\ max. 222 e=40,250) and inflections 245 15,350), 265(e=6,250) and 290 m (E=2,850).

Analysis-Calm. for C1'1H13C1N4 (percent): C, 66.13; H, 4.24; CI, 11.48;N, 18.15. Found (percent): C, 66.05; H, 4.13; CI, 11.34; N, 18.00.

EXAMPLE 2 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] 1,4]benzodiazepine In the manner given in Example 1A, 50 g. of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione was heated with 38.9g. of acetic acid hydrazide in 1760 ml. of absolute ethanol for a periodof 24 hours. The reaction mixture was then cooled and concentrated togive a residue. The residue was treated with water and the aqueoussuspension filtered. The solids remaining on the filter were dissolvedin methylene chloride, the solution was dried over anhydrous potassiumcarbonate, evaporated and the residue recrystallized once from ethylacetate. The material thus obtained (in two crops: 30.7 g. of meltingpoint 225-226.5 C. and 4.13 g. of melting point 222-223 C.) was meltedunder nitrogen in an oil bath maintained at 250 C., cooled andcrystallized from ethyl acetate to give 25.5 g. (47.7%) of 8-chloro-1-methyl 6 phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine of meltingpoint 227.5 228.5 C.

EXAMPLE 3 8-chloro-1-methyl-6-(2,6-difluorophenyl)-4H-striazolo [4,3-a][1,4]benzodiazepine A solution of 6.0 g. (0.0186 mole) of 1,3-dihydro-7-chloro (2,6-difluorophenyl)-2H-1,4-benzodiazepine-2- thione and 4.14 g.(0.0558 mole) of acetic acid hydrazide in 250 ml. of l-butanol washeated under reflux. During the first hour a stream of nitrogen waspassed through the reaction mixture to remove the hydrogen sulfideformed. The heating was continued for 18 hours in a nitrogen atmosphere.The reaction mixture was concentrated, the residue poured into water,and extracted with methylene chloride. The organic layer was dried overanhydrous sodium sulfate. Removal of the solvent gave 6.8 g. of orangesolid which was recrystallized from ethanol to give in two crops 4.5 g.(70%) of 8-chloro-1-methyl-6- (2,6-difluorophenyl) 4H s triazolo[4,3-a][1,4]benzodiazepine of melting point 278-279.5 C.

Analysis.-Calcd. for C H ClF N (percent): C, 59.22; H, 3.22; Cl, 10.28;F, 11.02; N, 16.26. Found (percent): C, 59.41; H, 3.31; Cl, 10.32; F,11.06; N, 16.18.

By heating the reaction mixture at lower temperature (replacingl-butanol by ethanol) or for shorter periods of time, the open chainintermediate, 2-(2-acetylhydrazino)-7-chloro 5(2,6-difluorophenyl)-3H-1,4-benzodiazepine, can be isolated. Thismaterial, recrystallized from ethanol, has a melting point of 274-277 C.

Analysis.Calcd. for C H ClF N O (percent): C, 56.28; H, 3.61; Cl, 9.77;F, 10.47; N, 15.45. Found (percent): C, 56.02; H, 3.49; Cl, 9.78; F,10.62; N, 15.53.

EXAMPLE 4 8-chloro-l-methyl-6-(o-fluorophenyl)-4H-s-triazolo- ,3-a][1,4] benzodiazepine A solution of 1.52 g. (0.005 mole) of7-chloro-1,3-dihydro 5 (o fluorophenyl)-2H-1,4-benzodiazepine-2- thioneand 1.11 g. (0.015 mole) of acetic acid hydrazide in 50 ml. of l-butanolwas refluxed for 12 hours while bubbling a stream on nitrogen throughthe reaction mixture. The solvent was evaporated in vacuo and theresidue was treated with water and methylene chloride. The phases wereseparated and the organic layer was dried over anhydrous sodium sulfateand concentrated to an oil. The crude oil was triturated with ethylacetate-Skellysolve B hexanes and the resulting solid was filtered togive 1.32 g. of solid of melting point 202 -203 C. Crystallization fromethyl acetate-Skellysolve B hexanes yielded 1.13 g. (70%) of8-chloro-1-methyl-6-(o-fluorophenyl)-4H-striazolo [4,3-a] [1,4benzodiazepine of melting point 203 204" C.

Analysis.Calcd. for C H ClFN (percent): C, 62.49; H, 3.70; CI, 10.85; F,5.81; N, 17.15. Found (percent): C, 62.39; H, 3.87; Cl, 10.91; F, 6.03;N, 17.11.

EXAMPLE 5 1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepineLA stirred mixture ofll,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-Z-thione (4.49 g.; 0.0179mole), acetic acid hydrazide (3.98 g.; 0.0537 mole) and l-butanol (200ml.) was refluxed for 3.5 hours with a slow stream of nitrogen bubblingthrough the reaction mixture. The mixture was concentrated in vacuo andthe residue was suspended in Water and extracted with methylenechloride. The extract was dried over anhydrous potassium carbonate andconcentrated. Crystallization of the residue from ethyl acetate gave2.97 g. (60.6%) of 1-methyl-6-phenyl- 4H-s-triazolo[4,3-a][l,4]benzodiazepine of melting point 21621-8 C. The analytical sampleprepared by recrystallizing some of this material tErom ethyl acetatehad a melting point of 230-231" C. The ultraviolet spectrum (ethanol)had end absorption A max. 216 (e=34,550) and inflections 243 (e=13,550),and 280 mp. (e=4,300).

Analysis.Calcd. for C17H14N4 (percent): C, 74.43; H, 5.14; N, 20.43.Found (percent): C, 74.10; H, 5.18; N, 20.05.

EXAMPLE 6 8-chloro-1-propyl-6-phenyl-4H-s-triazolo[4,3 -a] 1,4]benzodiazepine In the manner given in Example 2, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione was heated in l-butanol withbutyric acid hydrazide and the resulting product heated to 250 C. togive 8-chloro-1-propyl-6- phenyl-4H s triazolo[4,3-a][1,4]benzodiazepineof melting point 176176.5 C. The ultraviolet spectrum (ethanol) had endabsorption 7\ max. 209 (e=40,450) and inflections 237 (e=14,900), 245(e=l5,850), 270 (e=5,75()) and 290 m (e=3,000).

Analysis.-Calcd. for C H ClN (percent): C, 67.75; H, 5.09; CI, 10.53; N,16.63. Found (percent): C, 67.96; H, 5.09; Cl, 10.63; N, 16.59.

EXAMPLE 7 8-chloro-1-isopropyl-6-phenyl-4H-s-triazolo- [4,3-a] [1,4]benzodiazepine -In the manner given in Example2,7-chloro-1,3-dihydro-S-phenyl-ZH-1,4-benzodiazepine-Z-thione is heatedin ethanol with isobutyric acid hydrazide and the resulting productheated to 250 C. to give 8-chloro-1-isopropyl-6- phenyl-4H-s-triazolo[4, 3-a] [1,4 benzodiazepine.

EXAMPLE 8 *8-chloro-1,6-diphenyl-4H-s-triazolo [4,3-a]- [1,4]benzodiazepine In the manner given in Example 2,7-chloro-1,3-dihydro-S-phenyl-ZH-1,4-benzodiazepine-Z-thione was heatedin ethanol with benzoic acid hydrazide and the resulting product heatedto 250 C. to give 8-chloro-1,6-diphenyl- 4H striazolo[4,3-a][1,4]benzodiazepine of melting point 193.5194.5 C.

Analysis.Calcd. for C H ClN (percent): C, 71.25; H, 4.08; CI, 9.56; N,15.11. Found (percent): C, 71.56; H, 4.17; CI, 9.63; N, 15.16.

EXAMPLE 9 1-benzyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine A mixture of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (5.74 g.; 0.200 mole), phenylacetic acidhydrazide (9.0 g.) and l-butanol (200 ml.) was refluxed for 5 hours witha slow stream of nitrogen bubbling through the reaction mixture. Themixture was concentrated in vacuo, and the residue was suspended inwater and stirred for one hour. The solid product was collected byfiltration and dissolved in methylene chloride. The solution was driedover anhydrous potassium carbonate and concentrated. Crystallization ofthe residue (from ethyl acetate-Skellysolve B hexanes gave 5.28 g.(68.6%) of 1-benzyl-8-chloro-6-phenyl-4H-s-triazolo[4,3- a][1,4]benzodiazepine of melting point 191-192 C. The analytical sampleprepared by recrystallizing some of this masterial from ethylacetate-Skellysolve B hexanes had a melting point of 192.5 -'193.5 C.The ultraviolet spectrum (ethanol) had end absorption A max. 221(e=35,850)

11 and inflections 248 (e=14,550), 265 (e=6,100) and 290 m (e=2,300).

Analysis.Calcd. for C H ClN, (percent): C, 71.77; H, 4.45; CI, 9.21; N,14.56. Found (percent): C, 71.77; H, 4.63; Cl, 9.32; N, 14.79.

EXAMPLE 10 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo [4,3-a]1,4]benzodiazepine In the manner given in Example 2,7-chl0ro-1,3-dihydro-S-phenyl-ZH-l,4-benzodiazepine2-thione was heatedin ethanol with propionic acid hydrazide and the resulting productheated to 250 C. to give 8-chloro-1-ethyl-6- phenyl-4H-s-triaz0lo[4,3-a] [1,4] benzodiazepine of melting point 231.5 232.5 C. Theultraviolet spectrum (ethanol) had end absorption max. 224 (e=39,250)and inflections 248 (e=15,l), 266 (e=6,900) and 290 III/.0 (=3,250).

Analysis.Calcd. for C H ClN (percent): C, 66.97; H, 4.68; Cl, 10.99; N,17.36. Found (percent): C, 66.73; H, 4.83; Cl, 10.92; N, 17.29.

EXAMPLE 1 1 1-methyl-6-pehnyl-8- trifluoromethyl -4H-s triazolo [4,3-a]1,4]benzodiazepine A stirred mixture of1,3-dihydro--phenyl-7-(trifluoromethyl)-2H-1,4-benzodiazepine-Z-thione(64.9 g.; 0.204 mole), acetic acid hydrazide (45.3 g.; 0.612 mole) andmethanol (2500 ml.) was refluxed under nitrogen for 24 hours; during thefirst two hours nitrogen was bubbled through the refluxing mixture. Themixture was concentrated in vacuo. A suspension of the residue in waterwas stirred for one, hour and filtered. The solid was dried at 30 C. invacuo to give 64 g. of crude 2-(2-acetylhydrazino) 7 (trifluoromethyl) 5phenyl 3H-1,4-benzodiazepine. This material was heated in batches of 20g. at 200 C. under reduced pressure (12 mm.) until the solid had meltedand bubbling had become slow. The oily product was combined and storedat 4 C. The crystalline material which resulted was collected byfiltration, washed with ether and dried to give 33.4 g. of crudeproduct. The mother liquor was chromatographed on silica gel (3 kg.)with 5% methanol-95% benzene (by wolume) to give additional product. Thecombined product was recrystallized from wet methylene chloride-ether intwo crops: 25.2 g., melting point 120.5127.5 C., and 12.8 g., meltingpoint 120-l27 C. of 1-methyl-6- phenyl 8 (trifluoromethyl)4H-s-triazolo[4,3-a] [1,4] benzodiazepine hydrate. The first crop hadultraviolet spectrum (ethanol) having 7\ max. 219 (e=31,400) andinflections 247 (s=13,l00) and 280 mu (6:3,850).

Analysis.Calcd. for C H F N (percent): C, 63.15; H, 3.83; F, 16.65; N,16.37. Found for hydrate (percent): C, 59.07; H, 4.88; F, 15.90; N,15.48; H O, 5.85. Corrected for H O (percent): C, 62.73; H, 4.49; F,16.90; N, 16.45.

Heating this product to 80 C. for a period of 72 hours at a pressure of12 mm. Hg gave water-free 1- methyl-6-phenyl-8-(trifluoromethyl) 4H striazolo- [4,3-a] [1,4] benzodiazepine.

EXAM PLE 12 1-methyl-8-nitro-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine A stirred mixture of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-Z-thione (2.97 g.; 0.01 mole), acetic acid hydrozide(2.21 g.; 0.03 mole) and l-butanol (100 ml.) was refluxed for 1.5 hourswith a slow stream of nitrogen bubbling through the reaction mixture.The resulting mixture was concentrated in vacuo. The residue wassuspended in water and extracted with methylene chloride. The extractwas dried over anhydrous potassium carbonate and concentrated in vacuo.The residue was chromatographed on silica gel (200 g.) with 2%triethylamine-3% methanol-% ethyl acetate (by volume). The product thusobtained was crystallized from methanol-ethyl acetate to give 0.83 g.(26%) of 1- methyl 8 nitro 6 phenyl 4H s triazolo[4,3-a][1,4]benzodiazepine of melting point 233-234 C. The analytical sampleprepared by recrystallizing this material from methanol-ethyl acetatehad a melting point of 231.5 -232.5 C. The ultraviolet spectrum(ethanol) had end absorption A max. 226 (e=2l,500) and 259 my.(e=18,850).

Analysis.CalCd. for C N N O (percent): C, 63.94; H, 4.10; N, 21.93.Found (percent): C, 64.05; H, 3.85; N, 21.76.

EXAMPLE 13 Ethyl 8-chloro-6-phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine-l-carboxylate A mixture of 7-chloro 1,3dihydro-5-phenyl-2H-1,4- benzodiazepine-Z-thione (1.95 g.; 0.0068 mole),monoethyl oxalate hydrazide (2.7 g.; 0.0204 mole) and 1- butanol (50ml.) was refluxed under nitrogen for 7 hours and concentrated in vacuo.The residue was suspended in water and extracted with methylenechloride. The extract was dried over anhydrous potassium carbonate andconcentrated. The residue was chromatographed on silica gel (200 g.)with 60% ethyl acetate-40% Skellysolve B hexanes (by volume); -ml.fractions were collected. Fractions 36-60 were concentrated and theresidue was crystallized from ethyl acetate-Skellysolve B hexanes togive 0.41 g. of ethyl 8-chloro-6-phenyl-4H-striazolo [4,3-a][1,4]benzodiazepine-l-carboxylate of melting point 234-235.5 C. (dec.).The analytical sample was prepared by recrystallizing this material fromethyl acetate-Skellysolve B hexanes and had a melting point of 234-235C. (dec.). The ultraviolet spectrum (ethanol) had end absorption andinflections 223 (e=28,900), 250(6=19,100)8.11d2901'l1ll.(6=3,150)-Analysis.Calcd. for C H ClN O (percent): C, 62.21; H, 4.12; Cl, 9.67; N,15.28. Found (percent): C, 62.32; H, 4.02; Cl, 9.61; N, 15.14.

EXAMPLE l4 *8-chloro-l-methyl-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a][1,4] benzodiazepine A mixture of 1.0 g. (0.0031 mole) of7-chloro-1,3-dihydro-S-(o-chlorophenyl) 2H 1,4 benzodiazepine-2- thione,0.8 g. (0.0108 mole) of acetic acid hydrazide and a 40 ml. of l-butanolwas heated at reflux temperature under nitrogen for 24 hours. During thefirst 5 hours the nitrogen was slowly bubbled through the solution.After cooling and removing the solvent in vacuo, the product was wellmixed with water and collected on a filter, giving 0.9 g. of orangesolid, melting point 210-212 C. This was heated under nitrogen in an oilbath at 250 C. and then cooled. The solid was crystallized from ethylacetate, giving 0.5 g. of tan solid of melting point 215- 216 C. (dec.).This was dissolved in 25 ml. of 2-propanol, filtered, concentrated to 10ml. and cooled, yielding 0.46 g. (43%) of tan, crystalline8-chloro-1-methyl- 6-(o-chlorophenyl) 4H striazolo[4,3-a][1,4]benzodiazepine of melting point 223 -225 C.

Analysis.-Calcd. for C H Cl N (percent): C, 59.49; H, 3.52; CI, 20.66;N, 16.32. Found (percent): C, 59.55; H, 3.78; Cl, 20.72; N, 16.24.

EXAMPLE 15 8-ethyl-1-phenyl-6- (o-chlorophenyl) -4H-s-triazolo- [4,3-a][1,4] benzo diazepine In the manner given in Example 2,7-ethyl-1,3-dihydro- 5(o chlorophenyl) 2H 1,4 benzodiazepine-Z-thione isheated in ethanol with benzoic acid hydrazide and the resulting productheated to 250 C. to give 8-ethyl-1- 13 phenyl-6-(o-chlorophenyl) 4H striazolo[4,3-a] [1,4] benzodiazepine.

EXAMPLE 16 7-ethylthio-1-methyl-6-(o-bromophenyl)-4H-s-triazol0- [4,3-a][l,4]benzodiazepine In the manner given in Example 2, 6-ethylthio-1,3-dihydro-S-(o-bromophenyl) 2H 1,4-benzodiazepine-2- thione is heated inethanol with acetic acid hydrazide and the resulting product heated to250 C. to give 7-ethylthio-1-methyl-6-(o-bromophenyl) 4Hs-triazolo[4,3-a] [1,4]benzodiazepine.

EXAMPLE l7 10-tri-fluoromethyl -6- [p- (propionylamino) phenyl]4H-striazolo [4,3-a] 1,4 benzodiazepine In the manner given in Example2, 9-(trifiuoromethyl)- 1,3 dihydro 5 [p (propionylamino)phenyl]-2H-1,4-benzodiazepine-2-thione is heated in ethanol with formic acid hydrazideand the resulting product heated to 250 C. to givel-(trifiuoromethyl)-6-[p-(propionylamino) phenyl]-4H-s-triazolo[4,3-a][1,4] benzodiazepine.

EXAMPLE 1'8 7-ethylthio-l-ethyl-6- (o-bromophenyl)-4H-s-triazolo-[4,3-a] [1,4] benzodiazepine In the manner given in Example 2,6-ethylthio-1,3-dihydro (o-bromophenyl) 2H 1,4 benzodiazepine- 2-thioneis heated in ethanol with propionic acid hydrazide and the resultingproduct heated to 250 C. to give 7 ethylthio 1 ethyl 6 (0 bromophenyl)4H striazolo[4,3-a] [1,4] benzodiazepine.

EXAMPLE l9 9-propoxy-8-bromo-1-benzyl-6-[m-(ethylsulfinyD-phenyl]4H-s-triazolo [4,3-a] 1,4]benzodiazepine In the manner given in Example2, 8-propoxy-7-bromo- 1,3-dihydro 5[m-(ethylsulfinyl)phenyl]-2H-l,4-benzodiazepine-Z-thione is heated inethanol with phenylacetic acid hydrazide and the resulting productheated to 250 C. to give 9-propoXy-8-bromo 1 benzyl 6 [m-(ethylsulfinyl)phenyl] -4H-s-triazolo [4,3-a] 1,4] benzodiazepine.

EXAMPLE 20 -(dipropylamino)-7 methyl1-isopropyl-6-[m-(propylsulfonyl)phenyl]-4H-s triazolo-[4,3-a][1,4]benzodiazepine In the manner given in Example 2, 9-(dipropylamino)-6-methyl-1,3 dihydro-S-[m (propylsulfonyl)phenyl]-2H-1,4-benzodiazepine-Z-thione is heated in l-propanol with isobutyricacid hydrazide and the resulting product heated to 250 C. to give10-(dipropylamino)-7-methyll-isopropyl 6[m-(propylsulfonyl)phenyl]-4H-s-triazolo- [4,3-a] 1,4]benzodiazepine.

EXAMPLE 21 9-cyano-1-propyl-6- [p- (trifluoromethyl phenyl] -4H-s-triazolo [4,3-a] [1,4] benzodiazepine In the manner given in Example2, 8-cyano-l,3-dihydro-S-[p (trifluoromethyl)phenyl] 2H1,4-benzodiazepine-2-thione is heated in ethanol with butyric acidhydrazide and the resulting product heated to 250 C. to give9-cyan0-1-propyl-6- [p-(trifiuoromethyl phenyl] -4H- s-triazolo [4,3-a]1,4]benzodiazepine.

EXAMPLE 22 9-nitro-1-phenyl-6-(o-chlorophenyl)-4H-striazolo- [4,3-a][1,4] benzodiazepine In the manner given in Example 2,8-nitro-1,3-dihydro-5 (o-chlorophenyl) 2H l,4benzodiazepine-2- thione isheated in ethanol with benzoic acid hydrazide and the resulting productheated to 250 C. to give 9- 14 nitro-1-phenyl-6-(o-chlorophenyl)4H-s-triazolo[4,3-a] [1,4] benzodiazepine.

EXAMPLE 23 7,10=dich1oro-1-methyl-6-(p-isopropylphenyl)-4H- s-triazolo[4,3-a] [1,4] benzodiazepine In the manner given in Example 2,6,9-dichloro-1,3- dihydro-5 (p-isopropylphenyl) 2H-l,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and theresulting product heated to 250 C. to give 7,10- dichloro-l-methyl-6-(p-isopropylphenyl) 4H striazolo [4,3-a] 1,4] benzodiazepine.

EXAMPLE 24 4-methyl-8-bromol-isopropyl- 6- (o-fluorophenyl)4-H-s-triazolo [4,3-a] [1,4] benzodiazepine In the manner given inExample 2, 3-methyl-7-bromo- 1,3-dihydro-5-(o-fluorophenyl) 2H1,4-benzodiazepine- 2-th'ione is heated in ethanol with isobutyric acidhydrazide and the resulting the product heated to 250 C. to give4-methyl-8-bromo-1-isopr0pyl-6-(o-fluorophenyl)- 4H-s-triaz0lo [4,3-a][1,4]benzodiazepine.

EXAMPLE 25 EXAMPLE 26 10- (propylsulfonyl -8-methyll-ethyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine In the manner given inExample 2, 9-(propylsulfonyl)- 7-methyl-l,3-dihydro 5phenyl-ZH-1,4-benzodiazepine- 2-thione is heated in ethanol withpropionic acid hydrazide and the resulting product heated to 250 C. togive 10-(propylsulfony1) 8-methyl-1-ethyl-6-phenyl-4I-I- s-triazolo[4,3-a] [1,4] benzodiazepine.

EXAMPLE 27 8- (dimethylamino)-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine In the manner given in Example 2, 7-(dimethylamino)-1,3-dihydro-5-phenyl 2H 1,4-benzodiazepine-Z-thione is heated in ethanolwith formic acid hydrazide and the resulting product is heated to 250 C.to give S-(dimethylamino)-6-phenyl-4H s triazolo[4,3-a][l,4]benzodiazepine.

EXAMPLE 28 7, IO-dichloro-1-phenyl-6-(p-isopropylphenyl)- 4H-s-triazolo[4,3-a] [1,4] benzodiazepine In the manner given in Example 2,6,9-dichloro-1,3- dihydro-S-(p-isopropylphenyl) 2H 1,4-benzodiazepine-2-thione is heated in ethanol with benzoic acid hydrazide and theresulting product heated to 250 C. to give 7,10-dichloro 1phenyl-6-(p-isopropylphenyl)-4H-triazolo[4,3-a] [1,4] benzodiazepine.

EXAMPLE 29 7,9-diethyl-1-benzyl-6- (m-ethylphenyl)-4H- s-triazolo[4,3-a] [1,4] benzodiazepine In the manner given in Example 2,6,8-diethyl-1,3- dihydro-S-(m-ethylphenyl) 2H 1,4-benzodiazepine-2-thione is heated in ethanol with phenylacetic acid hydrazide and theresulting product heated to 250 C. to give 7,9-diethyl-1-benzyl'6-(m-ethylphenyl)-4I-I-s-triazolo [4,3-a] [1,4]benzodiazepine.

1 EXAMPLE 30 7-nitr0-1-methyl-6-(o-cyanophenyl) -4H-striazolo [4,3-a][1,4] benzodiazepine In the manner given in Example 2,6-nitro-1,3-dihydro- 5-(o-cyanophenyl) 2H 1,4-benzodiazepine-Z-thione isheated in ethanol with acetic acid hydrazide and the resulting productheated to 250 C. to give 7-nitro-1- methyl-6-o-(cyanophenyl) 4Hs-triazolo[4,3-a][1,4] benzodiazepine.

EXAMPLE 31 8- (dipropylamino -6- (o-nitrophenyl -4H- s-triazolo [4,3-a][1,4] benzodiazepine 'In the manner given in Example 2,7-(dipropylamino)- 1,3-dihydro-5-(o-nitrophenyl) 2H 1,4-benzodiazepine-2-thione is heated in ethanol with formic acid hydrazide and theresulting product heated to 250 C. to give 8-(dipropylamino)-6-(o-nitrophenyl) 4H s-triazolo[4,3- a] [1,4]benzodiazepine.

EXAMPLE 32 (acetylamino 1-ethyl-6- (p-cyanophenyl 4H-s-triazolo [4,3-a][1,4] benzodiazepine In the manner given in Example 2,9-acetylamino-1,3- dihydro-S-(p-cyanophenyl)-2H 1,4 benzodiazepine-2-thione is heated in ethanol with propionic acid hydrazide and theresulting product heated to 250 C. to give 10 (acetylamino) 1-ethyl-6-(pcyanophenyl) 4H-s-triazolo [4,3-a] [1,4]benzodiazepine.

EXAMPLE 33 Butyl 8-chloro-6- (m-nitrophenyl) -4H-s-triazolo [4,3-a][1,4] benzodiazepinel-carboxylate In the manner given in Example 13, amixture of 7- chloro-1,3-dihydro-5-(m-nitrophenyl) 2H1,4-benzodiazepine-Z-thione, monobutyl oxalate hydrazide and 1- butanolis refluxed under nitrogen for 7 hours to give butyl8-chloro-6-(m-nitrophenyl)-4H-s triazolo[4,3-a]1,4]benzodiazepine-l-carboxylate.

EXAMPLE 34 Methyl 9-fluoro-6- 2,4-dichlorophenyl -4H-s-triazolo [4,3-a][1,4]benzodiazepine-l-carboxylate In the manner given in Example 13, amixture of 8- fiuoro-1,3-dihydro 5(2,4-dichlorophenyl)-2H-1,4-benzodiazepine-Z-thione, monoethyl oxalatehydrazide and l-butanol is refluxed under nitrogen for 7 hours to givemethyl 9 fiuoro '6-(2,4-dichlorophenyD-4H s-triazolo [4,3-a][1,4]benzodiazepine-l-carboxylate.

EXAMPLE 35 8-chl0ro-6-pheny1-4H-s-triazolo [4,3-a] [1,4] benzodiazepineA mixture of 5.74 g. (0.020 mole) of7-chloro-1,3-dihydro-S-phenyl-ZH-1,4-benzodiazepine 2 thione, 3.6 g.(0.060 mole) of formic acid hydrazide and 200 ml. of 1- butanol Wasrefluxed for 3.75 hours with a slow stream of nitrogen bubbling throughthe mixture. The mixture was concentrated, the residue was suspended inwater, and the suspension was filtered. The filter cake consistedprincipally of unchanged starting material. The filtrate wasconcentrated, ethyl acetate and Skellysolve B hexanes being added duringthe concentration, giving crude product (2.54 g.) of melting point220.5-225 C. Recrystallization of this material from ethylacetate-Skellysolve B hexanes gave 8-chloro 6phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 228-2290C. The ultraviolet spectrum (ethanol) had end absorption A max. 222(e=40,950) and inflections at 245 (e=16,200) and 285 m (e=3,500).

Analysia-Calcd. for C H ClN (percent): C, 65.20; H, 3.76; CI, 12.03; N,19.01. Found (percent): C, 65.26; H. 3.56; Cl, 12.30; N, 18.95.

In the manner given in the preceding examples, other 1,3dihydro-5-phenyl-2H-1,4-benzodiazepine-Z-thiones of formula I can becondensed with acid hydrazide II, as defined earlier, to give other new6-phenyl 4H-s-triazolo [4,3-a][1,4]benzodiazepines. Representativecompounds thus obtained include:

10-chloro-1-methyl-6-(m-isopropylphenyl)-4H-s-triazolo [4,3-a] [1,4]benzodiazepine;

9-(dipropylamino) -1-phenyl-6-[p-(propionylamino) phenyl] -4H-s-triazolo[4,3-a] 1,4] benzodiazepine;

8- (methylsulfinyl -1-benzyl-6- (o-nitrophenyl -4H-striazolo [4,3-a][1,4] benzodiazepine;

7- (ethylsulfonyl) 1-propyl-6- (o-cyanophenyl -4Hs-triazolo [4,3-a][1,4] benzodiazepine;

4-propy1-1-isopropyl-6- [m-(methylthio)phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine;

10-fluoro-7-chloro-1-ethyl-6- [p-trifluoromethyl)phenyl]- 4H-s-triazolo[4,3-a] [1,4] benzodiazepine;

7,9-diethoxy-1-methyl-6-(m-ethoxyphenyl) -4H-s-triazolo [4, 3-a] [1,4benzodiazepine;

7- (propylthio -6- (m-iodophenyl -4H-s-triazolo [4,3-a]

[ 1,4] benzodiazepine;

8- (acetylamino -6- (p-iodophenyl) -4H-s-triazolo [4,3-a]

[1,4] benzodiazepine;

4-propyl- 6- (o-iodophenyl) -4H-s-triazolo [4,3-a] 1,4] benzodiazepine;

4-ethyl- 1-methyl-6- [o- (ethylthio pheny1-4H-s-triazolo [4,3-a][1,4]benzodiazepine;

4-methyl-7, 1 O-dichloro- 1-ethyl-6-(m-isopropoxyphenyl) 4H-s-triazolo[4,3-a] [1,4] benzodiazepine;

9-(propionylamino) -1-propyl-6- [m-propylthio)phenyl]- 4H-s-triazolo[4,3-a] [1,4] benzodiazepine;

7-diisopropylamino)-1-phenyl-6- [pdipropylamino) phenyl] -4H-s-triazolo[4,3-a] [1,4] benzodiazepine; and

4-isopropyl-7,9-diiodo-1-benzyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4]benzodiazepine;

8-chloro- 1-methyl-6- (3 ,4-dimethylphenyl) -4H-s-triazolo [4,3-a] [1,4]benzodiazepine;

6-( 2-methyl-4-methoxyphenyl -4H-s-triazolo [4,3-a] [1,4]

benzodiazepine;

8-methylthio-1-methyl-6-pheny1-4H-s-triazolo [4,3-a] 1,4]

benzodiazepine;

8-methoxy-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] 1,4]

benzodiazepine; and the like. What is claimed is: 1. A 2-2-acylhydrazino) 5 phenyl-3 H- 1,4-benzodiazepine of the Formula III:

wherein R is'selected from the group consisting of hydrogen, alkyl of 1to 3 carbon atoms, inclusive, phenyl, benzyl and --COOR' in which R' isalkyl of 1 to 4 carbon atoms, inclusive; wherein R is selected from thegroup consisting of hydrogen and alkyl of 1 to 3 carbon atoms,inclusive; and wherein R R R and R are selected from the groupconsisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive,halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkanoylamino and dialkylamino in whichthe carbon chain moieties are of 1 to 3 carbon atoms,inclusive.

2. The compound of claim 1 wherein R is methyl, R R R and R are hydrogenand R is 7-chloro and the compound is therefore2-(2-acetylhydrazino)-7-chlor0-5- phenyl-SH-1,4-benzodiazepine.

3. The compound of claim 1 wherein R is methyl, R and R are hydrogen, Ris 2-fiuoro, R is 6-fluoro, R is 7-chloro and the compound is therefore2-(2-acetylhydrazino)-7-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine.

References Cited UNITED STATES PATENTS 18 OTHER REFERENCES Deriez etal., J. Chem. Soc. (London), Part C, 1968, pp. 1103-4105.

5 ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

260-2393 D, 308 R, 562 N, 562 B, 562 P, 570 AB; 424-269 Page 1 UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 5,741,957

DATED 3 June 26, 1975 |NVENTOR(5 3 Jackson B Hester, J r.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, l ine 15, "Formula lV" should read -Formula (lV)--=; l i ne42, "Formula I should read --Fo rmula l Column 2, line 61,"bezodiazeplne" should read -benzodiazepine--; line 72,

''Compound E l l to Compound lV" should read --Compound (I l l toCompound (lV)-=-. Column 5, line 61, "50/ should read "50%"; l ine 65,"st'ychnine" should read --strychnine--; l'i ne 69, "styrchni ne" shouldread strychni ne-; 1 i ne 71, "am uscl e should read --a muscle--.Column 4, line 6, "4H-2" should read --4H-sl ine 12, "[4,5-]" shouldread [4,5a]--; l ine 14, (0- should read -(o l ine 14, "0.046 0.056should read --0.056 0.016--.; line 25/24, "(laccose)" should read--(lactose)--; l ine 62, "1,4" should read -1,5--. Column 5, line 15,"(ethylsulfineyl) should read -(ethylsulflnyl)--;

' line 16, "2H-1,4" should read ==2H-l,4-; l ine 25, )2H" should read--=)-2H; line 27, ")2H" should read --)-2H-; line 42, "benzodiazepie"should read --benzodiazepine--; l i ne 60, benzadiaze ine" should read-benzodiazepine-. Column 6,

l i ne 1, "0t should read -to--; l i ne 27, "2 '6' should read --2,6--;line 29, "none.-To" should read --none to-; line 60, "phenone.-/-\"Should read -phenone A--. Column 7, line 2, "phenone.-To" should read--phenone To-; line 12, "H, 2.25" should read --H, 2.55; line 16,"phenone.-L" should read -phenone L--; line 16, "(5500 ml should read(550 ml.)--;

l l ne 51, "2one.-A' should read -one A--; l ine 56, "phenyl (-2H'should read phenyl)-2H--. Column 8, line 61, "222 e=" should read--222(e= Column 10, line 75, masterial should read -material Col umn 11,l i ne 24, "pehnyl should read -phenyl line 69, "hydrozide" should read-hydrazide--. Column 15, line 14, "10-tri should read --10-(trl l ine14, "p henyl]4H" should read henyl] -4H-, Column'14, line 65, 4H-tri"should read H-s-tri- Column 15, l ine 9, "6-o-(" should read --6-(oline47, "monoethyl" should read --monomethyl-;

line 69, "2290" should read "229 Column 16, line 15,

G Page 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENTNO. 3,741,957

DATED June 26, 1975 INVENTOR(S) Jackson B. Hester, Jr.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

' "phenyiiH" should read --phenyl]-4H--; line 17, "p-tri" should readp(tri--; line 27, "phenyI- IH" should read henyl]-4H-; line 52, "[m-pro"should read --[m-(pro-; line 54, 'Y-di" should read --7(di--.

. Signed and Scaled this twent- [SEAL] yflrs D y Of Octorberl975 Arrest:

RUTH c. MAKSON C. MARSHALL DANN A nesting ()fjzcer Commissioneroflatenrs and Trademarks

